A genetic study of the FMR1 gene in a Sardinian multiple sclerosis population.

Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55-200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45-60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS.

The implication of neuroactive steroids in Tourette's syndrome pathogenesis: A role for 5α-reductase?

Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G × E × S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalysing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesise that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the 'backdoor' pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS.

[Cancer risk among shift workers: a review]. / Rischio oncogeno nei lavoratori a turni: analisi della letteratura.

INTRODUCTION: According to IARC, shift work resulting in disruption of circadian rhythm is a probable human carcinogen (Group 2A). METHODS: We examined the scientific literature on the carcinogenic risk among shift workers for risk assessment purposes. RESULTS: Clock genes polymorphisms might contribute with suppression of melatonin synthesis, immuno-suppression from sleep deprivation, individual habits associated with shift work, and low vitamin D levels, in increasing risk of breast cancer, prostate cancer and lymphoma among shift workers. CONCLUSION: Although the epidemiological evidence seems scanty, the hypothesis that shift work-related sleep deprivation would contribute to increasing cancer risk seems based on solid ground.

Behavioral, neuropsychiatric and cognitive disorders in Parkinson's disease patients with and without motor complications.

BACKGROUND: Parkinson's disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated. OBJECTIVE: To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC. METHODS: Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia. RESULTS: 349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p < 0.001), anxiety, depression and psychoses (p < 0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p < 0.001) and motor complications (12.2% - p < 0.05). Dyskinesias were significantly more present in patients with hypersexuality (p < 0.05) and compulsive shopping (p < 0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p < 0.001), with the exception of delusional jealousy. DISCUSSION: We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications.

Defective cerebral gamma-aminobutyric acid-A receptor density in patients with systemic lupus erythematosus and central nervous system involvement. An observational study.

Gamma-aminobutyric acid-A (GABA-A) receptors play a crucial role in regulating neuronal excitability and cognitive functions. Single-photon emission computerized tomography (SPECT) analysis of GABA-A receptors binding by (123)I-labelled Iomazenil ((123)I-IMZ) has been applied in some neuropsychiatric disorders to investigate conditions where GABA-A receptor density can be detected in several pathophysiological conditions. In this study we investigate cerebral GABA-A receptor density in a small series of patients with systemic lupus erythematosus (SLE) and cognitive impairment characterized by recurrent, episodic memory loss. Nine female patients with SLE and cognitive alterations underwent to a clinical neuropsychiatric evaluation including digital video-EEG, brain MRI, (99m)Tc-ECD brain SPECT and (123)I-IMZ brain SPECT. All patients tested showed diffuse or focal GABA-A receptor density reduction. This is, to our knowledge, the first report on GABA-A receptor density abnormalities associated with cognitive defects in SLE patients. We hypothesize that in our series a decrease in GABA-A receptor density might be related to the neurological manifestations. Further studies are needed to clarify this aspect and the possible mechanisms. GABA-A receptor density impairment might be due to the SLE-related cerebral vasculopathy, or to neuronal-reacting auto-antibodies or drugs which could interfere with GABA-A receptors expression/binding. This study may support the concept that cognitive impairment in systemic lupus erythematosus could be the outcome of fine-tuned neurotransmission alterations.

Vagal nerve stimulation improves cerebellar tremor and dysphagia in multiple sclerosis.

Vagus nerve stimulation (VNS), an adjunctive approach for the treatment of epilepsy, was performed in three multiple sclerosis (MS) patients displaying postural cerebellar tremor (PCT) and dysphagia. Following VNS, improvement of PCT and dysphagia was manifested over a period of two and three months, respectively. In view of the involvement of the main brainstem visceral component of the vagus, the nucleus tractus solitarius (NTS), in modulating central pattern generators (CPGs) linked to both olive complex pathway and swallowing, improvement is likely to be VNS related. The results obtained suggest an additional therapeutic application for VNS and may represent a novel form of treatment in patients with severe MS.

Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation.

OBJECTIVE: Though vagus nerve stimulation (VNS) is an important option in pharmaco-resistant epilepsy, its mechanism of action remains unclear. The observation that VNS desynchronised the EEG activity in animals suggested that this mechanism could be involved in VNS antiepileptic effects in humans. Indeed VNS decreases spiking bursts, whereas its effects on the EEG background remain uncertain. The objective of the present study is to investigate how VNS affects local and inter regional syncronization in different frequencies in pharmaco-resistant partial epilepsy. METHODS: Digital recordings acquired in 11 epileptic subjects 1 year and 1 week before VNS surgery were compared with that obtained 1 month and 1 year after VNS activation. Power spectrum and synchronization were then analyzed and compared with an epileptic group of 10 patients treated with AEDs only. RESULTS: VNS decreases the synchronization of theta frequencies (P < 0.01), whereas it increases gamma power spectrum and synchronization (< 0.001 and 0.01, respectively). CONCLUSIONS: The reduction of theta frequencies and the increase in power spectrum and synchronization of gamma bands can be related to VNS anticonvulsant mechanism. In addition, gamma modulation could also play a seizure-independent role in improving attentional performances. SIGNIFICANCE: These results suggest that some antiepileptic mechanisms affected by VNS can be modulated by or be the reflection of EEG changes.

Comparison of MRI, EEG, EPs and ECD-SPECT in Wilson's disease.

OBJECTIVES: The purpose of this study is to evaluate the efficiency of a few methodologies in detecting anatomo-functional brain abnormalities in patients with Wilson's disease. MATERIALS AND METHODS: Twenty-three patients with Wilson's disease underwent almost simultaneously brain magnetic resonance imaging (MRI), computerized electroencephalography (EEG), multimodal evoked potentials (EPs) and ECD single photon computerized tomography (SPECT) evaluation. The clinical picture was of the neurologic type in 8 patients and of the hepatic type in 15. RESULTS: MRI was abnormal in 7 patients with neurological manifestations. The EPs proved pathologic in 7 neurologically symptomatic patients and in 4 cases with hepatic form. These results agree with those reported in other case studies. The EEG records were abnormal only in 3 cases. Nevertheless, the most interesting finding of this study is the particular frequency (86%) of diffuse or focal decrease of ECD uptake shown by brain SPECT. CONCLUSION: We highlight the use of this interesting procedure in the therapeutic monitoring of this disease.

Correlation between cerebral perfusion and hyperventilation enhanced focal spiking activity.

Single photon emission computed tomography (SPECT) has frequently been used to investigate cerebral brain perfusion (CBP) occurring ictally and inter-ictally in epileptic patients. Several studies have addressed the multimodal analysis of the modifications occurring in cerebral areas involved in seizure activity, by correlating SPECT with electroencephalografic (EEG) recordings during ictal and inter-ictal epileptiform lateralized discharges (IELDs). Although these studies have yielded interesting results, variations in regional CBP (rCBP) observed during ictal events are difficult to interpret since the areas of altered rCBP might reflect not only events restricted to the epileptogenic focus, but also large fluctuations determined by seizure spread. Inter-ictal rCBP correlates with the area generating the local EEG epileptogenic activity in a limited percentage of studies. Hyperventilation (HPV) represents a well established EEG activation procedure aimed at enhancing epileptiform discharges. Since HPV-enhanced IELDs may help analyze the CBP pathophysiology in inter-ictal epilepsy, in the present study we investigate this specific aspect co-registering EEG with SPECT in subjects affected by partial epilepsy responding to HPV with IELD enhancement without seizure precipitation. This study suggests a correlation between localized increase in rCBP and HPV-induced IELDs and provides a tool to discuss uncommon aspects of the physiology of rCBP during the inter-ictal state in the epileptogenic areas.

Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy.

A conjugal case of amyotrophic lateral sclerosis (ALS) observed in Sardinia, Italy is reported. This is believed to be the ninth such observation described in the literature. The couple had lived together for 38 years in a house adjacent to the distillery they owned. No exogenous factors were revealed which could explain the genesis of the disease in either patients. Particularly, exposure to alcohol does not appear to have been involved in causing ALS. On the basis of statistical and epidemiological evaluations, the most likely explanation is that this association was purely coincidental.

Hippocampal theta activity after systemic administration of a non-peptide delta-opioid agonist in freely-moving rats: relationship to D1 dopamine receptors.

Hippocampal theta activity was acquired and processed off-line from digitized EEG recordings after subcutaneous (s.c.) administration of the non-opioid delta agonist BW 373U86 (0.5-2.5 mg/kg) in freely-moving rats. Relative theta power spectral analysis, implemented by a signal processing software, showed that BW 373U86 induced a dose-dependent increase in the slow component of theta band (Type 2 theta), while movement-related fast theta band (Type 1 theta) failed to show significant changes. Moreover, the increase in relative Type 2 theta power showed a maximal change at 1 mg/kg of BW 373U86, while higher doses, although effective in increasing relative Type 2 theta, induced locomotion and irregularly increased Type 1 hippocampal theta activity. The administration of 10.0 mg/kg of the delta antagonist Naltrindole (NLI) 30 min before BW 373U86, abolished hippocampal Type 2 theta increase. The rise of relative Type 2 theta power induced by BW 373U86 (1-2.5 mg/kg) was greatly attenuated by 0.1 mg/kg of the selective dopamine (DA) D1 antagonist SCH 23390. Administration of 0.1 mg/kg of SCH 23390 alone did not modify hippocampal Type 2 theta. These results indicate that delta receptors modulate the expression of hippocampal Type 2 theta and dopamine, through D1 receptors, exerts a permissive role on this influence.

5-HT1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5-HT1A receptors.

Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT1A agonists 8-OH-DPAT (5-20 micrograms/kg) and ipsapirone (20-100 micrograms/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and 100 micrograms/kg), which acts as an agonist at presynaptic (somatodendritic) 5-HT1A receptors and as an antagonist at postsynaptic 5-HT1A receptors. Power spectral analyses showed that all three compounds produced a dose-dependent increase in the EEG power occurring in the theta frequency band (3.5-8.0 Hz) as a proportion of total power from 0.25 to 30.0 Hz (relative theta power). The increase in relative theta power produced by 8-OH-DPAT (20 micrograms/kg) was greatly attenuated by spiperone (1 mg/kg), a highly effective 5-HT1A autoreceptor antagonist. Administration of spiperone alone had no significant effect on relative theta power. These results are discussed in relationship to the effects of these drugs on serotonergic neuronal activity. Our results suggest that preferential activation of presynaptic 5-HT1A receptors, and subsequent inhibition of serotonin neurotransmission, facilitates the appearance of hippocampal theta activity in awake cats.

C-Fos expression as a molecular marker in corticotropin-releasing factor-induced seizures.

Expression of Fos-like protein has been shown to increase after seizures in several types of experimentally induced epilepsies. The intracerebroventricular (icv) injection of murine corticotropin-releasing factor (CRF) in rats (10 micrograms), shows an electroencephalographic (EEG) spiking activity restricted to the amygdaloid-hippocampal area. This EEG seizure pattern represents a unique model of localized epileptic activity induced by a neuropeptide. C-fos expression after icv CRF has been considered a useful tool in mapping areas involved in stress and in seizure activity. Our results show that 1 microgram and 10 micrograms CRF are able to induce c-fos activation in several brain areas. Moreover, the present study not only details c-fos expression increase in brain areas directly involved in spiking activation, such as the amygdaloid-hippocampal region, but also maps the possible contribution of other regions to seizure manifestations.

A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements.

A subgroup of approximately 25% of dorsal raphe nucleus serotonergic neurons in cat was strongly activated in association with oral-buccal movements, such as chewing, licking, and grooming. The mean magnitude of increase in neuronal activity for these cells was approximately 100% above the spontaneous waking level. However, some of these cells were activated by as much as 200-300%. The neuronal activation frequently preceded the initiation of the movement and stopped abruptly in association with either pauses in the motor sequence or with its cessation. Most of the neurons in this subgroup were also strongly and preferentially activated by somatosensory stimuli applied to the head, neck, and face. During orientation to a strong or novel stimulus, the activity of these neurons fell silent for periods of 1-5 s. These data and results from our previous studies of medullary raphe neurons are discussed within the context of the general role of serotonin in tonic and central pattern generator-related motor activity.

Failure of naloxone to modify electroencephalogram interictal epileptiform discharges in patients with primary generalized epilepsy after slation.

Sleep deprivation (SD) is a method widely used to activate EEG epilept oform activity, but the basis of this effect remains unknown. One possibilty is that SD shares a common mechanism with physical and psychological stresses that also precipitate seizures. Because endogenous opioids are released during stress, opioids may play a role in enhancing epileptiform EEG patterns after SD. We report the effects of SD on EEG epileptiform activity in a small but highly homogeneous population of 13 epileptic patients with idiopathic (primary) generalized epilepsy (IGE). SD increased EEG interictal epileptiform discharges (IEDs); this activation was not modified by naloxone (NAL). Our results, in contrast to those of previous investigations of localization-related epilepsy, which showed an increase in IEDs after NAL administration, suggest a possible difference in the mechanism whereby SD enhances IEDs in IGE and localization-related epilepsy.

Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep-wake cycle in freely moving cats.

The variations of Acetylcholine (ACh) release in the cerebral cortex and dorsal hippocampus were monitored by microdialysis during the electroencephalographically recorded sleep-waking cycle in freely moving cats. The results show a state-dependent variation in ACh output in both the cortex and the hippocampus. ACh release increased by approximately 100% during quiet waking (QW) and by 175% during active waking (AW) as referred to slow wave sleep (SWS) baseline. In contrast, a clear difference between the two areas was observed during REM sleep. During this stage ACh release in the cortex reached approximately the same values observed during QW, while in the hippocampus ACh release rose to about 4-fold the level obtained during SWS or twice that of QW. The results support the idea that the increase in ACh release in the cortex reflects the desynchronized EEG of wakefulness and REM sleep, while the marked increase of ACh during REM in the hippocampus may be related to the sustained theta activity in this area.

Single-unit responses of serotonergic dorsal raphe neurons to 5-HT1A agonist and antagonist drug administration in behaving cats.

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was recorded in free-moving cats in response to i.v. administration of 5-hydroxytryptamine (5-HT)1A agonist and antagonist drugs. The 5-HT1A agonist drugs 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), ipsapirone, buspirone and 5-methoxy-N,N-dimethyltryptamine produced a rapid, dose-dependent inhibition of neuronal activity. 8-OH-DPAT (ED50 = 1.5 micrograms/kg) was approximately 45 times more potent than ipsapirone, buspirone or 5-methoxy-N,N-dimethyltryptamine (ED50 range = 6.0-6.8 micrograms/kg) in producing inhibition, and all drugs were more effective when cats were inactive (e.g., drowsiness) than during periods of behavioral arousal (e.g., active waking). Administration of the 5-HT1A autoreceptor antagonist spiperone (0.25 and 1 mg/kg) produced a rapid, dose-dependent increase in the firing rate, suggesting that under physiological conditions serotonergic neurons are controlled by tonic feedback inhibition. This effect was evident during wakefulness (a period of relatively high neuronal activity), but not during sleep (a period of relatively low neuronal activity). Spiperone also blocked the inhibitory action of 8-OH-DPAT in a dose- and time-dependent manner. There was a strong positive correlation between the magnitude of spiperone-induced neuronal activation and blockade of 8-OH-DPAT-induced neuronal suppression. These effects of spiperone cannot be attributed to its dopaminergic D2 or serotonergic 5-HT2 antagonist properties, because administration of haloperidol and ritanserin produced no increase in neuronal activity and did not block the action of 8-OH-DPAT. These results confirm the marked sensitivity of serotonergic dorsal raphe nucleus neurons to selective 5-HT1A agonist compounds in unanesthetized animals and suggest that 5-HT1A somatodendritic autoreceptors exert a tonic inhibitory influence on the firing rate of these neurons during periods of behavioral activation, but not during periods of behavioral quiescence.

Effects of the putative 5-hydroxytryptamine1A antagonists BMY 7378, NAN 190 and (-)-propranolol on serotonergic dorsal raphe unit activity in behaving cats.

Recent evidence from our laboratory has demonstrated that blockade of somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors by systemic administration of spiperone increases the firing rate of central serotonergic neurons in awake cats. The present study examines the effects of three other putative 5-HT1A antagonists (BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5]decane-7,9-dione), NAN 190 [1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine) and (-)-propranolol) on the single-unit activity of serotonergic neurons recorded in the dorsal raphe nucleus of free-moving cats. Systemic administration of the phenylpiperazine derivatives BMY 7378 (5-100 micrograms/kg i.v.) and NAN 190 (5-250 micrograms/kg i.v.) produced a rapid, dose-dependent inhibition of neuronal activity with BMY 7378 being approximately twice as potent as NAN 190 (ED50 = 15.3 micrograms/kg vs. 34.2 micrograms/kg). The suppression of neuronal activity produced by both compounds was greatly attenuated by spiperone (1 mg/kg i.v.). Systemic administration of (-)-propranolol (2 and 4 mg/kg i.v.) produced a modest suppression of serotonergic neuronal activity which did not appear to be dose-related. The ability of BMY 7378, NAN 190 and (-)-propranolol to block the suppression of neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist, was also examined. Pretreatment with these compounds had no significant effect on the inhibitory response of serotonergic neurons to 8-OH-DPAT challenge. These results indicate that BMY 7378 and NAN 190 act as agonists rather than antagonists at the somatodendritic 5-HT1A autoreceptor.(ABSTRACT TRUNCATED AT 250 WORDS)